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Kim Y et al. (2008) PINK1 controls mitochondrial localization of Parkin through direct phosphorylation. Biochem. Biophys. Res. Commun. 377(3): 975-980 Sen A et al. (2015) Clueless, a protein required for mitochondrial function, interacts with the PINK1-Parkin complex in Drosophila. Dis. Model. Mech. 8(6): 577-589 Cox RT and Spradling AC (2009) clueless, a conserved Drosophila gene required for mitochondrial subcellular localization, interacts genetically with parkin. Dis. Model. Mech. 2(9-10): 490-499 Summary Parkinson’s disease is caused by the loss of dopaminergic neurons within the substantia nigra of the brain linked to declines in mitochondrial function. Protection of mitochondrial integrity is ensured by the PINK1-Parkin pathway which is present in both, Drosophila and human. This pathway contains the kinase PINK1 and the E3 ubiquitin ligase Parkin which are frequently mutated in the disease. Therefore, the first question to clarify was the detailed relationship between PINK1 and Parkin. In human neuroblastoma cell line, the researchers found that PINK1 induces Parkin localization to the mitochondria in its kinase activity-dependent manner through direct phosphorylation of Parkin in its linker region. This translocation is important for mitochondrial integrity, so the authors suggested that PINK1-associated Parkinson’s Disease is caused by reduced amount of Parkin in the mitochondria. These results were confirmed in an in vivo assay in Drosophila demonstrating that this pathway is well conserved between humans and the Drosophila system. Since the PINK1-Parkin pathway plays a major role in Parkinson’s Disease, the gene clueless which functions in mitochondrial localization probably through this pathway was further analyzed. Flies mutant for clueless displayed abnormal mitochondrial structure and function that lead to flight muscle and metabolic defects similar to those found in flies mutant for parkin or pink1. Further analysis of clueless mutants revealed mitochondrial clustering in the anterior region of the cell. Similar results could be observed in parkin mutants and they could show that clueless and parkin interact genetically to promote mitochondrial clustering. In addition, clueless and parkin mutants revealed high-level changes in gene expression, mainly in genes protecting from reactive oxygen species or that are important for DNA repair and apoptosis. To further study the mechanism of clueless in the PINK1-Parkin pathway, the relationship between clueless and pink1 was examined in Drosophila. A genetically interaction between both was suggested by the phenotype which was pronounced in double-heterozygous mutants with pink1 and clueless mutations. Epitasis analysis revealed that clueless functions upstream of parkin and downstream of pink1 in cell culture and in vivo. Further analysis showed, that under normal conditions clueless and pink1 form a complex on the outer mitochondrial membrane whereas under stress conditions pink1 and parkin form a complex. Additional investigations showed that a lack of clueless decreases mitochondrial protein levels and by acting as a negative regulator clueless prevents the interaction between pink1 and parkin. In conclusion, the researchers suggest that healthy mitochondria have associated Clueless particles, undergo normal mitochondrial protein import and have low levels of PINK1. Whereas under disrupted protein import, Clueless particles are lost, PINK1 is stabilized on the outer mitochondrial membrane and is able to recruit Parkin by its direct phosphorylation. Thus, the PINK1-Parkin pathway is very important for maintaining the mitochondrial integrity in humans and flies. The crucial role of this pathway makes it an attractive target for the treatment against the development of Parkinson’s Disease.